Advanced Endometrial Cancer: Future Directions in Care

EP: 1.Overview: A 70-Year-Old Woman With Advanced Endometrial Cancer

EP: 2.Endometrial Cancer: Risk Factors and Diagnostic Work-up

EP: 3.Treatment Armamentarium for Advanced Endometrial Cancer

EP: 4.KEYNOTE-158: Pembrolizumab Use in Advanced Endometrial Cancer

EP: 5.Advanced Endometrial Cancer: Optimal Sequencing of Therapy

EP: 6.Combination Pembrolizumab-Lenvatinib in Advanced Endometrial Cancer

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EP: 7.Advanced Endometrial Cancer: Future Directions in Care

Case: A 70-Year-Old Woman With Endometrial Cancer

Initial Presentation

• A 70-year-old postmenopausal woman presents after experiencing abnormal uterine bleeding for about 3 months. She has a grown daughter, underwent menopause at 52 years of age, and her father had prostate cancer in his late 60’s.
• PMH: Unremarkable
• PE: Notable for large uterus and tenderness upon palpation

Clinical work-up

• Endometrial biopsy: endometrioid adenocarcinoma, FIGO grade 1
• Surgery: ELAP TAH BSO with bilateral pelvic node dissection
• Pathology: grade 2 endometrioid adenocarcinoma, 15 negative pelvic nodes, invasive 1.9 cm of 2.4 cm myometrium
• Molecular testing shows MSI-high, MMR proficient, and HER2-

Treatment

• Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
• 12 months after completing radiotherapy, she presented with new RLE edema and right hydroureter
• She then was treated with carboplatin/paclitaxel chemotherapy which was well tolerated

Treatment

• 15 months later the patient has disease relapse with metastases to the paraaortic lymph nodes
• She is now treated with pembrolizumab

Transcript:

Michael Birrer, MD, PhD: There’s a tremendous amount of excitement in the field, and I share it. The first direction is moving all these agents up front and getting them up earlier in the treatment of endometrial cancer. We can take pembrolizumab—we now have dostarlimab approved also—and move it up earlier, closer to the initial diagnosis, combining it with chemotherapy. A patient gets a biopsy. It’s positive. They get surgery, but they’re at higher risk. They would get adjuvant chemotherapy if they’re microsatellite unstable, for sure. It makes a lot of sense to add an I/O [immuno-oncology] agent at that point, which would likely increase the fraction of patients who never recur. That’s the first step: moving them all up front. I don’t think we’re going to see much from a toxicity standpoint. For tumors that are microsatellite stable, it’s the same thing, moving lenvatinib-pembrolizumab up front. It may even be better than carboplatin-paclitaxel because of the data we have so far. The patient gets diagnosed, and they’re at high risk for recurrence. Instead of getting adjuvant chemotherapy, they might get adjuvant lenvatinib-pembrolizumab.

The second direction is to move them up front. A lot more patients are going to benefit, but some aren’t. The questions become, “Why are they not responding to immunotherapy? What are the mechanisms of resistance? Can we combine I/O combinations with other I/O targets, or can we use I/O with other agents other than lenvatinib to improve the response rate?” That’s going to be a little trickier than what I just said. What I just said about moving it up front—all that is happening. We’ve got randomized phase 3 trials ongoing. But what I just described is going to require some hard-core biology. We need to biopsy those tumors and look at them. If they’re microsatellite unstable but not responding to single-agent I/O, what’s the mechanism of that? Why is that happening? Is it that T cells aren’t trafficking into the tumor? Is it that they have a different target or mechanism other than PD-1? The whole field of immuno-oncology has matured to the point that we’re looking a little further downstream in terms of mechanisms of resistance.

Patients with endometrial cancer have been a forgotten group of patients. It was mostly a postmenopausal patient population, many of whom had hypertension, diabetes, and heart problems. It’s not a huge market, so companies stayed away. We’re over that—companies are in there—but I’m not sure the oncology field recognizes that. I still get patients referred to me whose oncologist said that with endometrial cancer recurring after chemotherapy, there’s nothing to offer. We need to bang the drum and make it clear that terrific results from KEYNOTE-158 and KEYNOTE-775 are home runs.

Transcript edited for clarity.